Zaninello, Roberta (2015) Genetic variants involved in blood pressure response to losartan identified by GWAS methodology. Doctoral Thesis.
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Aim: to identify genetic variants involved in blood pressure response to Losartan, an angiotensin II receptor blocker, with a whole genome approach.
Methods: n=722 never treated patients from Italy (SOPHIA study) with Essential Hypertension (EH): Losartan 50 mg o.d. was prescribed for 4 weeks to 539 patients. A genome-wide association study and imputation were perfomed on 494 patients. After quality control 372 patients remained for analysis To confirm the specificity of our findings, we tested their association with deltaSBP at 4wks in 458 patients treated with HCTZ. The best markers were tested for replication in two independent cohorts of hypertensives from the GERA2 and GENRES studies.
Results: 131 SNPs were associated with deltaSBP4 (P≤10-5), 121 of them to diastolic BP response. A peak of association in the Calcium/Calmodulin-dependent protein Kinase I D gene (CAMK1D) was identified: rs10752271 showed an effect size of -5.5±0.94mmHg and a P=1.2x10-8). No association was found in HCTZ samples. In GENRES the association was confirmed (P=0.04, effect size=-5.3±2.5mmHg).
Conclusion: The rs10752271 polymorphism in the CAMK1D gene may represent a novel tool for individualized antihypertensive treatment. The Calcium/Calmodulin-dependent protein Kinase I, CAMKI, belongs to the regulatory pathway involved in aldosterone synthesis. Circulating aldosterone levels were directly associated with an increase in blood pressure and the development of hypertension (Framingham Offspring Study).
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